Pharmaceutical formulations containing substituted 2-aryl-aminoacetic acid compounds and/or substituted 2-heteroaryl-aminoacetic acid compounds

ABSTRACT

Pharmaceutical formulations containing substituted 2-aryl-aminoacetic acid compounds and/or substituted 2-heteroaryl-aminoacetic acid compounds corresponding to formula I, as well as to their use in the production of drugs and in related methods of treating or inhibiting pain and neurodegenerative disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/EP2004/001062, filed Feb. 5, 2004, designating the United Statesof America, and published in German as WO 2004/071381 A2, the entiredisclosure of which is incorporated herein by reference. Priority isclaimed based on German Patent Application No. 103 06 202.5, filed Feb.13, 2003.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical preparations containingsubstituted 2-arylaminoacetic acid compounds and/or substituted2-heteroarylaminoacetic acid compounds and the use thereof for theproduction of pharmaceutical preparations and in related methods oftreatment.

BACKGROUND OF THE INVENTION

Pain is one of the basic clinical symptoms. There is a worldwide needfor effective pain treatments. The urgency of the requirement fortherapeutic methods for providing tailored and targeted treatment ofchronic and non-chronic pain, this being taken to mean pain treatmentwhich is effective and satisfactory from the patient's standpoint, isevident from the large number of scientific papers relating to appliedanalgesia and to basic nociception research which have appeared inrecent times.

Conventional opioids, such as for example morphine, are effective in thetreatment of severe to very severe pain, but they exhibit unwantedaccompanying symptoms, such as for example respiratory depression,vomiting, sedation, constipation or the development of tolerance.Moreover, they are less effective in treating neuropathic or incidentalpain, which is in particular experienced by tumour patients.

Opioids exert their analgesic effect by binding to membrane receptorsbelonging to the family of G protein-coupled receptors. There aremoreover further receptors and ion channels which play a role in thesystem governing the genesis and transmission of pain, such as forexample the N-methyl-D-aspartate (NMDA) ion channel, via which asubstantial proportion of synaptic communication proceeds and by whichcalcium ion exchange between a neuronal cell and its surroundings iscontrolled.

Knowledge about the physiological significance of ion channel-selectivesubstances has been obtained by the development of the patch-clamptechnique with which the action of NMDA antagonists on the calciumbalance in the cell's interior may be detected.

SUMMARY OF THE INVENTION

One object underlying the present invention was accordingly to providenovel pharmaceutical preparations which are in particular suitable forcombatting pain, preferably chronic and/or neuropathic pain, and whichpreferably do not exhibit the undesired accompanying symptoms whichoccur with opioids or at least exhibit them to a reduced extent.

This object has been achieved by the provision of the pharmaceuticalpreparations according to the invention containing at least onesubstituted 2-arylaminoacetic acid compound and/or at least onesubstituted 2-heteroarylaminoacetic acid compound of the general formulaI below.

The present invention accordingly provides a pharmaceutical preparationcontaining at least one substituted 2-arylaminoacetic acid compoundand/or at least one substituted 2-heteroarylaminoacetic acid compound ofthe general formula I,

in which R¹ denotes a monocyclic aryl or heteroaryl residue, which maybe at least monosubstituted and/or fused with an optionally at leastmonosubstituted monocyclic or polycyclic ring system optionallycomprising at least one heteroatom as a ring member, and R² denotes amonocyclic aryl residue, which may be at least monosubstituted and/orfused with an optionally at least monosubstituted monocyclic orpolycyclic ring system optionally comprising at least one heteroatom asa ring member, in each case optionally in the form of one of the purestereoisomers thereof, in particular enantiomers or diastereomers, theracemates thereof or in the form of a mixture of stereoisomers, inparticular the enantiomers or diastereomers, in any desired mixingratio, or in each case in the form of the acids thereof or the basesthereof or in the form of the physiologically acceptable salts thereof,in particular sodium salts or hydrochloride salts, or in each case inthe form of the solvates thereof, in particular hydrates.

For the purposes of the present invention, a mono- or polycyclic ringsystem is taken to mean mono- or polycyclic hydrocarbon residues, whichmay be saturated, unsaturated or aromatic. If a polycyclic ring systemis present, it may also comprise in different rings two or morecorresponding substructures exhibiting a different degree of saturation.The mono- or polycyclic ring system may optionally also comprise one ormore heteroatoms as ring members, wherein the different rings of thepolycyclic ring system may comprise identical or different heteroatoms.If a polycyclic ring system is present, the individual rings thereof arepreferably fused with one another.

The substituted 2-arylaminoacetic acid compounds and/or substituted2-heteroarylaminoacetic acid compounds of the general formula I whichmay preferably be considered for the pharmaceutical preparationsaccording to the invention are those in which the residue R¹ denotes a5- or 6-membered, monocyclic aryl or heteroaryl residue, which may be atleast monosubstituted and/or fused with an optionally at leastmonosubstituted mono-, di- or tricyclic ring system optionallycomprising at least one heteroatom as a ring member, wherein the ringsof the ring system are in each case 5- to 7-membered, preferably denotesan optionally at least monosubstituted phenyl, naphthyl, furanyl,thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl,quinolinyl or isoquinolinyl residue, particularly preferably denotes aphenyl residue which is unsubstituted or preferably identicallysubstituted in 3,5-position, and R² has the above-stated meaning, ineach case optionally in the form of one of the pure stereoisomersthereof, in particular enantiomers or diastereomers, the racematesthereof or in the form of mixtures of the stereoisomers, in particularthe enantiomers or diastereomers, in any desired mixing ratio, or ineach case in the form of the acids thereof or the bases thereof or inthe form of the physiologically acceptable salts thereof, in particularsodium salts or hydrochloride salts, or in each case in the form of thesolvates thereof, in particular hydrates.

The substituted 2-arylaminoacetic acid compounds and/or substituted2-heteroarylaminoacetic acid compounds of the general formula I whichmay likewise preferably be considered for the pharmaceuticalpreparations according to the invention are those in which the residueR² denotes a 5- or 6-membered monocyclic aryl residue, which may be atleast monosubstituted and/or fused with an optionally at leastmonosubstituted mono-, di- or tricyclic ring system optionallycomprising at least one heteroatom as a ring member, wherein the ringsof the ring system are in each case 5- to 7-membered, preferably denotesa phenyl residue, which may be at least monosubstituted and/or fusedwith an optionally at least monosubstituted mono- or dicyclic ringsystem optionally comprising at least one heteroatom as a ring member,wherein the rings of the ring system are in each case 5- or 6-membered,and R¹ has the above-stated meaning, in each case optionally in the formof one of the pure stereoisomers thereof, in particular enantiomers ordiastereomers, the racemates thereof or in the form of mixtures of thestereoisomers, in particular the enantiomers or diastereomers, in anydesired mixing ratio, or in each case in the form of the acids thereofor the bases thereof or in the form of the physiologically acceptablesalts thereof, in particular sodium salts or hydrochloride salts, or ineach case in the form of the solvates thereof, in particular hydrates.

The substituted 2-arylaminoacetic acid compounds and/or substituted2-heteroarylaminoacetic acid compounds of the general formula I whichare particularly preferably used in the pharmaceutical preparationsaccording to the invention are those in which the residue R² is selectedfrom the group consisting of dibenzofuran-4-yl, dibenzothiophen-4-yl,phenoxathiin-4-yl, thianthren-1-yl and phenyl, in each caseunsubstituted or at least monosubstituted, preferably from the groupconsisting of dibenzofuran-4-yl, dibenzothiophen-4-yl,phenoxathiin-4-yl, thianthren-1-yl, 2-methylsulfanylphenyl,3-methylsulfanylphenyl and 4-methylsulfanylphenyl, particularlypreferably from the group consisting of dibenzofuran-4-yl,dibenzothiophen-4-yl, phenoxathiin-4-yl and thianthren-1-yl, and R¹ hasthe above-stated meaning, in each case optionally in the form of one ofthe pure stereoisomers thereof, in particular enantiomers ordiastereomers, the racemates thereof or in the form of mixtures of thestereoisomers, in particular the enantiomers or diastereomers, in anydesired mixing ratio, or in each case in the form of the acids thereofor the bases thereof or in the form of the physiologically acceptablesalts thereof, in particular sodium salts or hydrochloride salts, or ineach case in the form of the solvates thereof, in particular hydrates.

If R¹ denotes an at least monosubstituted monocyclic aryl or heteroarylresidue and/or comprises an at least monosubstituted mono- or polycyclicring system, the corresponding substituents may, in each case mutuallyindependently, preferably be selected from the group consisting oflinear or branched, optionally at least monosubstituted, C₁₋₆ alkyloptionally attached via an oxygen atom or a sulfur atom, linear orbranched, optionally at least monosubstituted C₂₋₆ alkenyl, optionallyattached via an oxygen atom or a sulfur atom, linear or branched,optionally at least monosubstituted, C₂₋₆ alkynyl optionally attachedvia an oxygen atom or a sulfur atom, optionally at least monosubstitutedC₃₋₈ cycloalkyl optionally comprising at least one heteroatom,optionally attached via an oxygen atom or a sulfur atom, halogen, OH,SH, CN, optionally at least monosubstituted phenyl, naphthyl, furanyl,thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl,quinolinyl or isoquinolinyl optionally attached via an oxygen atom or asulfur atom. The substituents may particularly preferably be selectedfrom the group consisting of F, Cl, Br, I, OH, SH, unsubstituted C₁₋₆alkyl, unsubstituted C₁₋₆ alkoxy, C₁₋₆ perfluoroalkyl, C₁₋₆perfluoroalkoxy, unsubstituted C₁₋₆ alkylsulfanyl, C₁₋₆perfluoroalkylsulfanyl, unsubstituted phenylsulfanyl, unsubstitutedcyclopentyl and unsubstituted cyclohexyl.

If one of these above-stated substituents is itself mono- orpolysubstituted, the substituents thereof may preferably be selectedfrom the group consisting of F, Cl, Br, hydroxy, CN, CF₃, CHF₂ and CH₂F.

If R² denotes an at least monosubstituted monocyclic aryl residue and/orcomprises an at least monosubstituted mono- or polycyclic ring system,the corresponding substituents may, in each case mutually independently,preferably be selected from the group consisting of linear or branched,optionally at least monosubstituted, C₁₋₆ alkyl optionally attached viaan oxygen atom or a sulfur atom, linear or branched, optionally at leastmonosubstituted C₂₋₆ alkenyl, optionally attached via an oxygen atom ora sulfur atom, linear or branched, optionally at least monosubstituted,C₂₋₆ alkynyl optionally attached via an oxygen atom or a sulfur atom,optionally at least monosubstituted C₃₋₈ cycloalkyl optionallycomprising at least one heteroatom, optionally attached via an oxygenatom or a sulfur atom, halogen, OH, SH, optionally at leastmonosubstituted phenyl, naphthyl, furanyl, thiophenyl, pyrrolyl,imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl orisoquinolinyl optionally attached via an oxygen atom or a sulfur atom.The substituents may particularly preferably be selected from the groupconsisting of F, Cl, Br, I, OH, SH, unsubstituted C₁₋₆ alkyl,unsubstituted C₁₋₆ alkoxy, C₁₋₆ perfluoroalkyl, C₁₋₆ perfluoroalkoxy,unsubstituted C₁₋₆ alkylsulfanyl, C₁₋₆ perfluoroalkylsulfanyl,unsubstituted phenylsulfanyl, unsubstituted cyclopentyl andunsubstituted cyclohexyl.

If one of these above-stated substituents is itself mono- orpolysubstituted, the substituents thereof may preferably be selectedfrom the group consisting of F, Cl, Br, hydroxy, CN, CF₃, CHF₂ and CH₂F.

If one or more residues R¹ and/or R² denote(s) one of the above-statedresidues, which comprise one or more heteroatoms, these heteroatoms may,unless otherwise stated, preferably be selected from the groupconsisting of nitrogen, oxygen and sulfur. The heteroatoms areparticularly preferably oxygen and/or sulfur.

The pharmaceutical preparations according to the invention veryparticularly preferably contain at least one substituted2-arylaminoacetic acid compound and/or at least one substituted2-heteroarylaminoacetic acid compound of the general formula I selectedfrom the group consisting of:(dibenzofuran-4-yl)-(3,5-dichlorophenylamino)acetic acid,(dibenzothiophen-4-yl)-(3,5-dichlorophenylamino)acetic acid,(3,5-dichlorophenylamino)-(phenoxathiin-4-yl)acetic acid,(3,5-dichlorophenylamino)-(thianthren-1-yl)acetic acid,(3,5-dichlorophenylamino)-(2-methylsulfanylphenyl)acetic acid,(3,5-dichlorophenylamino)-(4-methylsulfanylphenyl)acetic acid and(3,5-bis(trifluoromethyl)phenylamino)-(dibenzothiophen-4-yl)acetic acid,in each case optionally in the form of one of the pure stereoisomersthereof, in particular enantiomers or diastereomers, the racematesthereof or in the form of mixtures of the stereoisomers, in particularthe enantiomers or diastereomers, in any desired mixing ratio, or ineach case in the form of the acids thereof or the bases thereof or inthe form of the physiologically acceptable salts thereof, in particularsodium salts or hydrochloride salts, or in each case in the form of thesolvates thereof, in particular hydrates.

It has surprisingly been found that the substituted 2-arylaminoaceticacid compounds and/or the substituted 2-heteroarylaminoacetic acidcompounds of the above general formula I exhibit an elevated affinityfor the glycineB binding site of the NMDA receptor channel and aresuitable as glycineB antagonists on the NMDA receptor complex forregulating the calcium balance of the cells in the transmission of painand thus inter alia also for regulating the perception of pain.

The pharmaceutical preparations according to the invention containing atleast one substituted 2-arylaminoacetic acid compound and/or at leastone substituted 2-heteroarylaminoacetic acid compound of the generalformula I in particular exhibit marked activity in combatting pain,preferably chronic and/or neuropathic pain.

The pharmaceutical preparations according to the invention containing atleast one substituted 2-arylaminoacetic acid compound and/or at leastone substituted 2-heteroarylaminoacetic acid compound of the generalformula I are moreover suitable for the treatment of anxiety states,inflammatory and/or allergic reactions, depression, abuse of drugsand/or medicines and/or alcohol, gastritis, diarrhoea, urinaryincontinence, cardiovascular diseases, respiratory diseases, coughing,mental health conditions, epilepsy, schizophrenia, neurodegenerativediseases, preferably Alzheimer's disease and/or Huntington's choreaand/or Parkinson's disease and/or multiple sclerosis, cerebralischaemia, cerebral infarcts, psychoses brought about by elevated aminoacid levels, strokes, cerebral oedema, hypoxia, anoxia, AIDS dementia,encephalomyelitis, Tourette's syndrome, tinnitus and perinatal asphyxia.

The substituted 2-arylaminoacetic acid compounds and the substituted2-heteroarylaminoacetic acid compounds used according to the inventionmay be produced using conventional methods known to the person skilledin the art, such as for example described in U.S. Pat. No. 6,232,467; WO00/24510; WO 01/55091; N. A. Petasis, L. A. Zavialov, J. Am. Chem. Soc.119, 445-446 (1997); N. A. Petasis, A. Goodman, I. A. Zavialov,Tetrahedron 53, 16463-16470 (1997), N. A. Petasis, S. Boral, TetrahedronLett. 42, 539-542 (2001) and G. S. Currie et al., J. Chem. Soc., PerkinTrans, 1 (2000), 2982-2990. The corresponding descriptions are herebyintroduced as a reference and are deemed to be part of the disclosure.

The substituted 2-arylaminoacetic acid compounds or substituted2-heteroarylaminoacetic acid compounds of the above general formula Iused according to the invention are preferably produced by reacting atleast one amine of the general formula II

in which R¹ has the above-stated meaning, with glyoxylic acid(OHC—COOH), optionally in the form of a hydrate, and at least oneboronic acid of the general formula III

in which R² has the above-stated meaning, in a suitable reaction medium,preferably in an organic solvent, particularly preferably in methylenechloride or a mixture containing methylene chloride, to yield at leastone compound of the general formula I and this is optionally purifiedand isolated using conventional methods known to the person skilled inthe art.

The above-described reaction preferably proceeds at a temperature of 15°C. to 30° C., particularly preferably at a temperature of 20 to 25° C.

The above-described process for the production of compounds of thegeneral formula I used in the pharmaceutical preparation according tothe invention has the advantage that the amines used of the generalformula II, the glyoxylic acid and the boronic acids of the generalformula III are soluble in the reaction medium, but the substituted2-arylaminoacetic acid compounds and the substituted2-heteroarylaminoacetic acid compounds of the general formula I incontrast are usually insoluble, such that they may be obtained in pureform by simple filtration and washing with the reaction medium used.

The substituted 2-arylaminoacetic acid compounds and substituted2-heteroarylaminoacetic acid compounds of the general formula I andcorresponding stereoisomers may be obtained using conventional methodsknown to the person skilled in the art in the form of thephysiologically acceptable salts thereof, wherein the pharmaceuticalpreparations according to the invention may comprise one or more saltsof one or more compounds of the general formula I.

If the compounds used according to the invention of the general formulaI assume the form of basic salts, these are preferably salts of alkalimetals, alkaline earth metals or ammonium salts, particularly preferablysodium, potassium, calcium, magnesium or ammonium salts, whereinammonium salts are taken to mean not only [NH₄]⁺ salts but also[NH_(x)R_(4-x)]⁺ salts with R═C₁₋₄ alkyl and x=0-3, very particularlypreferably sodium salts.

If the compounds used according to the invention of the general formulaI assume the form of acidic salts, these may be obtained, for example,by reaction with an inorganic or organic acid, preferably withhydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonicacid, formic acid, acetic acid, oxalic acid, succinic acid, tartaricacid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamicacid, saccharic acid, cyclohexanesulfamic acid, aspartame,monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinicacid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid,α-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/oraspartic acid. The hydrochloride salts of the compounds of the generalformula I used according to the invention are particularly preferred.

The corresponding hydrochloride salts may preferably be obtained byconverting the particular substituted 2-arylaminoacetic acid compoundand/or substituted 2-heteroarylaminoacetic acid compound of the generalformula I and/or corresponding stereoisomers into the correspondinghydrochloride salts by combination of the compounds of the generalformula I or corresponding stereoisomers in unprotonated form, dissolvedin a suitable organic solvent, such as for example butan-2-one (methylethyl ketone), with trimethylsilyl chloride (TMSCl) and water.

The substituted 2-arylaminoacetic acid compounds and/or2-heteroarylaminoacetic acid compounds of the general formula I andcorresponding stereoisomers may optionally be obtained in the form ofthe solvates thereof, preferably the hydrates thereof, usingconventional methods known to the person skilled in the art, as may thecorresponding acids, the corresponding bases or the salts of thesecompounds.

If the substituted 2-arylaminoacetic acid compounds and/or thesubstituted 2-heteroarylaminoacetic acid compounds of the generalformula I are obtained after the production thereof in the form of amixture of the stereoisomers thereof, preferably in the form of theracemates thereof or other mixtures of their various enantiomers and/ordiastereomers, these may be separated and optionally isolated byconventional methods known to the person skilled in the art. Exampleswhich may be mentioned are chromatographic separation methods, inparticular liquid chromatography methods at standard pressure or atelevated pressure, preferably MPLC and HPLC methods, and fractionalcrystallisation methods. Individual enantiomers, for examplediastereomeric salts formed by means of HPLC on a chiral phase or bymeans of crystallisation with chiral acids, for instance (+)-tartaricacid, (−)-tartaric acid or (+)-10-camphorsulfonic acid, may here inparticular be separated from one another.

The substituted 2-arylaminoacetic acid compounds and/or2-heteroarylaminoacetic acid compounds of the general formula I andcorresponding stereoisomers as well as in each case the correspondingacids, bases, salts and solvates are toxicologically safe and aretherefore suitable as pharmaceutical active ingredients inpharmaceutical preparations.

The present invention also provides the use of at least one substituted2-arylaminoacetic acid compound and/or at least one substituted2-heteroarylaminoacetic acid compound of the general formula I for theproduction of a pharmaceutical preparation for combatting pain,preferably neuropathic and/or chronic pain, for regulating the glycineBbinding site on the NMDA receptor complex and for the treatment ofanxiety states, inflammatory and/or allergic reactions, depression, theabuse of drugs and/or alcohol and/or medicines, gastritis, diarrhoea,urinary incontinence, cardiovascular diseases, respiratory diseases,coughing, mental health conditions, epilepsy, schizophrenia,neurodegenerative diseases, preferably of Alzheimer's disease and/orHuntington's chorea and/or Parkinson's disease and/or multiplesclerosis, cerebral ischaemia, cerebral infarcts, psychoses broughtabout by elevated amino acid levels, strokes, cerebral oedema, hypoxia,anoxia, AIDS dementia, encephalomyelitis, Tourette's syndrome, tinnitusand/or perinatal asphyxia.

The pharmaceutical preparations according to the invention may assumethe form of liquid, semisolid or solid dosage forms, for example in theform of solutions for injection, drops, succi, syrups, sprays,suspensions, tablets, patches, capsules, dressings, suppositories,ointments, creams, lotions, gels, emulsions, aerosols or inmultiparticulate form, for example in the form of pellets or granules,optionally press-moulded into tablets, packaged in capsules or suspendedin a liquid, and also be administered as such.

Apart from one or more substituted 2-arylaminoacetic acid compoundsand/or one or more substituted 2-heteroarylaminoacetic acid compounds ofthe general formula I, optionally in the form of the pure stereoisomersthereof, in particular enantiomers or diastereomers, the racematesthereof or in the form of mixtures of the stereoisomers, in particularthe enantiomers or diastereomers, in any desired mixing ratio, or ineach case in the form of the acids thereof or the bases thereof or inthe form of the physiologically acceptable salts thereof, in particularsodium salts or hydrochloride salts, or in each case in the form of thesolvates thereof, in particular hydrates, the pharmaceuticalpreparations according to the invention conventionally contain furtherphysiologically acceptable pharmaceutical auxiliary substances, whichare preferably selected from the group consisting of matrix materials,fillers, solvents, diluents, surface-active substances, dyes,preservatives, disintegrants, slip agents, lubricants, aromas andbinders.

Selection of the physiologically acceptable auxiliary substances and thequantities thereof which are to be used depends upon whether thepharmaceutical preparation is to be administered orally, subcutaneously,parenterally, intravenously, intraperitoneally, intradermally,intramuscularly, intranasally, buccally, rectally or topically, forexample onto infections of the skin, mucous membranes or eyes.Preparations in the form of tablets, coated tablets, capsules, granules,pellets, drops, succi and syrups are preferred for oral administration,while solutions, suspensions, readily reconstitutible dried preparationsand sprays are preferred for parenteral, topical and inhalatoryadministration.

Substituted 2-arylaminoacetic acid compounds and/or substituted2-heteroarylaminoacetic acid compounds of the general formula I,optionally in the form of the pure stereoisomers thereof, in particularenantiomers or diastereomers, the racemates thereof or in the form ofmixtures of the stereoisomers, in particular the enantiomers ordiastereomers, in any desired mixing ratio, or in each case in the formof the acids thereof or the bases thereof or in the form of thephysiologically acceptable salts thereof, in particular sodium salts orhydrochloride salts, or in each case in the form of the solvatesthereof, in particular hydrates, in a depot in dissolved form or in adressing, optionally with the addition of skin penetration promoters,are suitable percutaneous administration preparations.

Orally or percutaneously administrable formulations may also release theparticular substituted 2-arylaminoacetic acid compounds and/or thesubstituted 2-heteroarylaminoacetic acid compounds of the generalformula I, optionally in the form of the pure stereoisomers thereof, inparticular enantiomers or diastereomers, of the racemates thereof or inthe form of mixtures of the stereoisomers, in particular the enantiomersor diastereomers, in any desired mixing ratio, or in each case in theform of the acids thereof or the bases thereof or in the form of thephysiologically acceptable salts thereof, in particular sodium salts orhydrochloride salts, or in each case in the form of the solvatesthereof, in particular hydrates, in delayed manner.

The quantity the particular substituted 2-arylaminoacetic acid compoundsand/or the substituted 2-heteroarylaminoacetic acid compounds of thegeneral formula I, optionally in the form of the pure stereoisomersthereof, in particular enantiomers or diastereomers, the racematesthereof or in the form of mixtures of the stereoisomers, in particularthe enantiomers or diastereomers, in any desired mixing ratio, or ineach case in the form of the acids thereof or the bases thereof or inthe form of the physiologically acceptable salts thereof, in particularsodium salts or hydrochloride salts, or in each case in the form of thesolvates thereof, in particular hydrates, to be administered to patientsmay vary and is for example dependent on the weight or age of thepatient and on the mode of administration, the indication and theseverity of the complaint. Conventionally, 0.005 to 500 mg/kg,preferably 0.05 to 5 mg/kg of patient body weight of at least onesubstituted 2-arylaminoacetic acid compound and/or at least onesubstituted 2-heteroarylaminoacetic acid compound of the general formulaI is administered, optionally in the form of the pure stereoisomersthereof, in particular enantiomers or diastereomers, the racematesthereof or in the form of mixtures of the stereoisomers, in particularthe enantiomers or diastereomers, in any desired mixing ratio, or ineach case in the form of the acids thereof or the bases thereof or inthe form of the physiologically acceptable salts thereof, in particularsodium salts or hydrochloride salts, or in each case in the form of thesolvates thereof, in particular hydrates.

Pharmacological Methods

(a) Receptor Binding Study (GlycineB Binding Site of the NMDA ReceptorChannel)

The affinity of the compounds of the general formula I used according tothe invention for the glycine binding site of the NMDA receptor channelis determined using brain membrane homogenates (homogenate of cortex andhippocampus area from the brain of male rats, Wistar strain), as forexample described in B. M. Baron, B. W. Siegel, B. L. Harrison, R. S.Gross, C. Hawes and P. Towers, Journal of Pharmacology and ExperimentalTherapeutics, (1996), vol. 279, page 62. The corresponding literaturedescription is hereby introduced as a reference and is deemed to be partof the disclosure.

To this end, the cortex and hippocampus are dissected out of freshlyharvested rat brains and homogenised with ice cooling in 5 mmol/l ofTRIS-acetate buffer, 0.32 mol/l of sucrose, pH 7.4 (10 ml/g freshweight) using a Potter homogeniser (Braun/Melsungen, 10 piston strokesat 500 rpm) and then centrifuged for 10 minutes at 1,000 g and 4° C. Thefirst supernatant is collected and the sediment again homogenised withice cooling with 5 mmol/l of tris-acetate buffer, 0.32 mol/l of sucrose,pH 7.4 (5 ml/g of original fresh weight) with the Potter homogeniser (10piston strokes at 500 rpm) and centrifuged for 10 minutes at 1,000 g and4° C. The resultant supernatant is combined with the supernatant fromthe first centrifugation and centrifuged at 17.000 g for 20 minutes at4° C. The supernatant after this centrifugation is discarded and themembrane sediment resuspended with 5 mmol/l of TRIS-acetate buffer, pH8.0 (20 ml/g of original fresh weight) and homogenised with 10 pistonstrokes at 500 rpm.

The membrane homogenate is then incubated for 1 hour at 4° C. andcentrifuged for 30 minutes at 50,000 g and 4° C. The supernatant isdiscarded and the centrifuge tubes containing the membrane sediment aresealed with Parafilm and frozen for 24 hours at −20° C. On the followingday, the membrane sediment is thawed and resuspended with ice-cold 5mmol/l TRIS-acetate buffer, 0,1% saponin (wt./vol.), pH 7.0 (10 ml/g oforiginal fresh weight) and homogenised with 10 piston strokes at 500 rpmand then centrifuged for 20 minutes at 50.000 g and 4° C. The resultantsupernatant is discarded and the sediment resuspended in a small volumewith 5 mmol/l of TRIS-acetate buffer, pH 7.0 (approx. 2 ml/g of originalfresh weight) and again homogenised with 10 piston strokes at 500 rpm.After determination of the protein content, the membrane homogenate isadjusted with 5 mmol/l TRIS-acetate buffer, pH 7.0, to a proteinconcentration of 10 mg of protein/ml and frozen in aliquots until usedfor testing.

The receptor binding test is performed by thawing aliquots, dilutingthem 1:10 with 5 mmol/l TRIS-acetate buffer, pH 7.0, homogenising themwith ice-cooling with 10 piston strokes at 500 rpm with the Potterhomogeniser (10 piston strokes at 500 rpm) and centrifuging them for 60minutes at 55,000 g at 4° C. The supernatant is decanted and themembrane sediment adjusted with ice-cold 50 mmol/l TRIS-acetate buffer,pH 7.0, to a protein concentration of 1 mg/ml and again homogenised with10 piston strokes at 500 rpm and kept in suspension in an ice bath withstirring on a magnetic stirrer. This membrane homogenate is used in thereceptor binding test in a quantity of 100 □l per 1 ml batch (0.1 mg ofprotein/ml in the final batch). In the binding test, the buffer used was50 mmol/l TRIS-acetate buffer, pH 7.0, and the radioactive ligand was 1mmol/l of (³H)-MDL 105.519 (B. M. Baron et al., 1996). The level ofnonspecific binding is determined in the presence of 1 mmol/l ofglycine.

In further batches, the compounds used according to the invention areadded in concentration series and the displacement of the radioactiveligand from its specific binding at the glycine-binding site of the NMDAreceptor channel is determined. Each of the triplicate batches isincubated for 120 minutes at 4° C. and then harvested by filtrationthrough glass fibre filter mats (GF/B) in order to determine theradioactivity bound to the membrane homogenate. The radioactivityretained on the glass fibre filters is measured, after addition ofscintillating material (Ready Protein, Beckmann Coulter GmbH, Krefeld,Germany) in the β-counter (Packard TRI-CARB Liquid ScintillationAnalyzer 2000 CA, Packard Instrument, Meriden, Conn. 06450, USA).

(b) Formaldehyde Test (Mouse)

The investigations for determining the antinociceptive action of thesubstituted 2-arylaminoacetic acid compounds and/or substituted2-heteroarylaminoacetic acid compounds of the above general formula Iused according to the invention are carried out by the formaldehyde teston male albino mice (NMRI, 25-35 g, Iffa, Credo, Belgium).

In the formaldehyde test, a distinction is drawn between the first(early) phase (0-15 min after formaldehyde injection) and the second(late) phase (15-60 min after formaldehyde injection) (D. Dubuisson etal., Pain, vol. 4, pp. 161-174 (1977)). The early phase, being a directresponse to the formaldehyde injection, is considered to be a model ofacute pain, while the late phase is considered to be a model ofpersistent (chronic) pain (T. J. Coderre et al., Pain, vol. 52, pp.259-285 (1993)). The corresponding literature descriptions are herebyintroduced as a reference and are deemed to be part of the disclosure.

The compounds used according to the invention of the general formula Iare investigated in the second phase of the formaldehyde test in orderto obtain information regarding the action of the substances inchronic/inflammatory pain.

A nociceptive reaction is induced in the freely mobile test animals by asingle, subcutaneous formaldehyde injection (20 μl, 1 wt. % aqueoussolution) into the dorsal side of the rear hind paw, the reaction beingexpressed by distinct licking and biting of the affected paw.

For the investigation period in the second (late) phase of theformaldehyde test, nociceptive behaviour is continuously recorded byobserving the animals. Pain behaviour is quantified by summing theseconds for which the animals exhibit licking and biting of the affectedpaw over the investigation period. After injection of the compoundswhich are antinociceptively active in the formaldehyde test, thedescribed behaviours of the animals are reduced or even eliminated. Inthe same manner as in the tests, in which the animals receive aninjection of test compound before the formaldehyde, the control animalsare injected with vehicle, i.e. solvent (for example 0.9% NaCl solution)before administration of the formaldehyde. The behaviour the animalsafter administration of the substance (n=10 per compound dose) iscompared with a control group (n=10). On the basis of the quantificationof the pain behaviour, action in the formaldehyde test is determined asa percentage change of the control. ED₅₀ calculations are carried out byregression analysis. The time of administration before the formaldehydeinjection was selected as a function of the mode of administration ofthe compounds used according to the invention (intraperitoneal: 15 min;intravenous: 5 min).

The invention is explained below with reference to Examples. Theseexplanations are given merely by way of illustration and do not restrictthe general concept of the invention.

EXAMPLES

The chemicals and solvents used were purchased from conventionalsuppliers (Acros, Aldrich, Chempur, Fluka, Lancaster and Merck).

The NMR spectra were measured with spectrometers made by Bruker AnalytikGmbH, Silberstreifen 4, D-76287 Rheinstetten. The instrument names areas follows: for 300 MHz: Avance DPX 300 MHz, for 600 MHz: Avance DRX 600MHz.

The ESI mass spectra were measured with a Finnigan LCQ model instrumentmade by Thermoquest (Analytische Systeme GmbH, Boschring 12, D-63329Egelsbach) and evaluated with Xcalibur software.

General Synthesis Method for the Production of the OptionallySubstituted 2-arylaminoacetic Acid Compounds and/or OptionallySubstituted 2-heteroarylaminoacetic Acid Compounds of the GeneralFormula I used According to the Invention:

10 mmol of glyoxylic acid hydrate were dissolved in 50 ml ofdichloromethane, 10 mmol of the particular amine component of thegeneral formula II and 10 mmol of the particular boronic acid componentof the general formula III were added with stirring and stirredovernight at room temperature (approx. 20° C.-25° C.). The precipitatedreaction product was removed by suction filtration, washed with a littlecold dichloromethane and then dried under a high vacuum. Colourlesssolids were obtained.

Table 1 below shows the particular compound of the general formula Iproduced, together with the components of the general formulae II andIII used for the production thereof.

TABLE 1 Amine component of the Boronic acid component of Examplecompound general formula II the general formula III Example 1:(Dibenzofuran-4-yl)-(3,5- 3,5-dichlorophenylaminedibenzofuran-4-yl-boronic acid dichlorophenylamino)acetic acid Example.2: (Dibenzothiophen-4-yl)-(3,5- 3,5-dichlorophenylaminedibenzothiophen-4-yl-boronic dichlorophenylamino)acetic acid acidExample 3: (3,5-Dichlorophenylamino)- 3,5-dichlorophenylaminephenoxathiin-4-yl-boronic acid (phenoxathiin-4-yl)acetic acid Example 4:(3,5-Dichlorophenylamino)-(thianthren- 3,5-dichlorophenylaminethianthren-1-yl-boronic acid 1-yl)acetic acid Example 5:(3,5-Dichlorophenylamino)-(2- 3,5-dichlorophenylamine 2-methylsulfanyl-methylsulfanylphenyl)acetic acid phenylboronic acid Example 6:(3,5-Dichlorophenylamino)-(4- 3,5-dichlorophenylamine 4-methylsulfanyl-methylsulfanylphenyl)acetic acid phenylboronic acid Example 7:(3,5-Bis(trifluoromethyl)-phenylamino)- 3,5-bis(trifluoro-dibenzothiophen-4-yl-boronic (dibenzothiophen-4-yl)acetic acidmethyl)phenylamine acid

Example 1

(Dibenzofuran-4-yl)-(3,5-dichlorophenylamino)acetic acid

Yield: 3.86 g (100% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=5.69 ppm (d, 1H, α-CH); 6.62 ppm (s, 1H,aryl-H); 6.73 ppm (s, 2H, 2×aryl-H); 7.08 ppm (d, 1H, α-NH); 7.43 ppm(m, 2H, 2×aryl-H); 7.56 ppm (m, 2H, 2×aryl-H); 7.77 ppm (d, 1H, J=8.3Hz, aryl-H); 8.12 ppm (d, 1H, J=7.6 Hz, aryl-H); 8.16 ppm (d, 1H, J=7.6Hz, aryl-H); 13.22 ppm (s (wide), 1H, CO₂H).

ESI-MS: molar mass (calculated for C₂₀H₁₃Cl₂NO₃): 386.20 g/mol

Measured (positive mode): 385.9 (MH⁺); 340.1 (M-CO₂).

Measured (negative mode): 383.9 (M-H); 340.3 (M-CO₂),

Example 2

(Dibenzothiophen-4-yl)-(3,5-dichlorophenylamino)acetic acid

Yield: 4.02 g (100% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=5.44 ppm (d, 1H, α-CH); 6.60 ppm (s, 1H,aryl-H); 6.70 ppm (s, 2H, 2×aryl-H); 7.11 ppm (d, 1H, □-NH); 7.50 ppm(m, 2H, 2×aryl-H); 7.57 ppm (m, 1H, aryl-H); 7.67 ppm (m, 1H, aryl-H);8.03 ppm (m, 1H, aryl-H); 8.38 ppm (m, 2H, 2×aryl-H); 13.38 ppm (s(wide), 1H, CO₂H).

ESI-MS: molar mass (calculated for C₂₀H₁₃Cl₂NO₂S): 402.30 g/mol

Measured (positive mode): 401.8 (MH⁺); 356.1 (M-CO₂).

Measured (negative mode): 399.9 (M-H); 356.3 (M-CO₂).

Example 3

(3,5-Dichlorophenylamino)-(phenoxathiin-4-yl)acetic acid

Yield: 1.07 g (25.4% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=5.60 ppm (d, 1H, α-CH); 6.60 ppm (s, 1H,aryl-H); 6.71 ppm (s, 2H, aryl-H); 6.95 ppm (d, 1H, a-NH); 7.13 ppm (m,2H, aryl-H); 7.25 ppm (m, 1H, aryl-H); 7.28-74.0 ppm (m, 5H, aryl-H).

ESI-MS: molar mass (calculated for C₂₀H₁₃Cl₂NO₃S): 414.00 g/mol

Measured (positive mode): 417.8 (MH⁺).

Measured (negative mode): 416.1 (M-H); 372.4 (M-CO₂).

Example 4

(3,5-Dichlorophenylamino)-(thianthren-1-yl)acetic acid

Yield: 4.17 g (96% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=5.70 ppm (d, 1H, α-CH); 6.65 ppm (s, 2H,aryl-H); 7.25 ppm (d, 1H, α-NH); 7.30-7.50 ppm (m, 3H, aryl-H);7.55-7.70 ppm (m, 2H, aryl-H); 7.75 ppm (m, 1H, aryl-H); 13.40 ppm (s(wide), 1H, CO₂H).

ESI-MS: molar mass (calculated for C₂₀H₁₃Cl₂NO₂S₂): 431.00 g/mol

Measured (positive mode): 433.8 (MH⁺).

Measured (negative mode): 434.0 (M-H); 388.3 (M-CO₂).

Example 5

(3.5-Dichlorophenylamino)-(2-methylsulfanylphenyl)acetic acid

Yield: 3.27 g (95.5% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=2.55 ppm (s, 3H, SCH₃); 5.45 ppm (d, 1H,J=6.8 Hz, α-CH); 6.60 ppm (m, 3H, 3×aryl-H); 7.03 ppm (d, 1H, J=6.8 Hz,α-NH); 7.21 ppm (t, 1H, J=6.8 Hz, aryl-H); 7.35 ppm (m, 2H, J=7.5 Hz,2×aryl-H); 7.46 ppm (d, 1H, J=7.6 Hz, aryl-H); 13.11 ppm (s (wide), 1H,CO₂H).

ESI-MS: molar mass (calculated for C₁₅H₁₃Cl₂NO₂S): 342.25 g/mol

Measured (positive mode): 341.9 (MH⁺),

Measured (negative mode): 340.0 (M-H); 296.3 (M-CO₂).

Example 6

(3,5-Dichlorophenylamino)-(4-methylsulfanylphenyl)acetic acid

Yield: 2.96 g (86.5% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=2.46 ppm (s, 3H, SCH₃); 5.16 ppm (d, 1H,α-CH); 6.60 ppm (s, 1H, aryl-H); 6.67 ppm (s, 2H, aryl-H); 6.90 ppm (d,1H, α-NH); 7.26 ppm (d, 2H, J=8.3 Hz, aryl-H); 7.42 ppm (d, 2H, J=8.3Hz, aryl-H); 13.04 ppm (s (wide), 1H, CO₂H).

ESI-MS: molar mass (calculated for C₁₅H₁₃Cl₂NO₂S): 342.25 g/mol

Measured (negative mode): 340.0 (M-H); 296.3 (M-CO₂).

Example 7

(3,5-Bis(trifluoromethyl)phenylamino)-(dibenzothiophen-4-yl)acetic acid

Yield: 4.69 g (100% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=5.64 ppm (d, 1H, J=5.7 Hz, α-CH); 7.09 ppm(s, 1H, α-NH); 7.31 ppm (s, 2H, 2×aryl-H); 7.49-7.46 ppm (m, 4H,4×aryl-H); 7.72 ppm (d, 1H, J=7.1 Hz, aryl-H); 8.04 ppm (m, 1H, aryl-H);8.35-8.41 ppm (m, 2H, 2×aryl-H); 13.49 ppm (s (wide), 1H, CO₂H).

ESI-MS: molar mass (calculated for C₂₂H₁₃F₆NO₂S): 469.41 g/mol

Measured (negative mode): 468.0 (M-H); 424.5 (M-CO₂).

Measured (positive mode): 469.8 (MH⁺); 424.3 (M-CO₂).

General Synthesis Method for the Production of the Corresponding SodiumSalts of the Compounds of the General Formula I:

10 mmol of the particular substituted 2-arylaminoacetic acid compound orthe particular substituted 2-heteroarylaminoacetic acid compound of thegeneral formula I were suspended in a little water and 10 mmol 1-normalaqueous sodium hydroxide solution were added. In the event of poorsolubility, methanol was added dropwise until dissolution was complete.After 30 minutes' stirring at room temperature (approx. 20-25° C.), thesolution was evaporated in a rotary evaporator, the remaining solutionwas frozen at −60° C. in a mixture of isopropanol/dry ice andfreeze-dried. The sodium salts were obtained as colourless solids.

Example 8

(Dibenzofuran-4-yl)-(3-5-dichlorophenylamino)acetic acid, sodium salt

Yield: 3.37 g (82.5% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=5.64 ppm (d, 1H, α-CH); 6.60 ppm (s, 1H,aryl-H); 6.71 ppm (s, 2H, 2×aryl-H); 7.06 ppm (d, 1H, J=7.6 Hz, α-NH);7.43 ppm (m, 2H, 2×aryl-H); 7.54 ppm (m, 2H, 2×aryl-H); 7.76 ppm (d, 1H,J=8.3 Hz, aryl-H); 8.10 (d, 1H, J=7.6 Hz, aryl-H); 8.16 ppm (d, 2H,J=7.6 Hz, aryl-H).

Example 9

(Dibenzothiophen-4-yl)-(3,5-dichlorophenylamino)acetic acid, sodium salt

Yield: 4.00 g (94% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=4.70 ppm (m, 1H, α-CH); 6.45 ppm (s, 1H,aryl-H); 6.49 ppm (s, 2H, 2×aryl-H); 6.82 ppm (m, 1H, α-NH); 7.44 ppm(m, 3H, 3×aryl-H); 7.56 ppm (m, 1H, aryl-H); 7.96 ppm (m, 1H, J=6.8 Hz,aryl-H); 8.16 ppm (d, 1H, J=7.6 Hz, aryl-H).

Example 10

(3,5-Dichlorophenylamino)-(phenoxathiin-4-yl)acetic acid, sodium salt

Yield: 4.32 g (97.7% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=4.99 ppm (d, 1H, J=4.5 Hz, α-CH); 6.40 ppm(s, 1H, aryl-H); 6.49 ppm (s, 2H, 2×aryl-H); 6.72 ppm (d, 1H, J=5.3 Hz,α-NH); 6.97 ppm (m, 1H, aryl-H); 7.05 ppm (m, 1H, aryl-H); 7.12 ppm (m,1H, aryl-H), 7.17 ppm (m, 1H, aryl-H); 7.25-7.32 ppm (m, 3H, 3×aryl-H).

ESI-MS: molar mass (calculated for C₂₀H₁₄Cl₂NNaO₃S): 443.0 g/mol

Measured (negative mode): 418.0 (M-H—Na); 372.3 (M-Na—CO₂).

Example 11

(3,5-Dichlorophenylamino)-(thianthren-1-yl)acetic acid, sodium salt

Yield: 4.18 g (87.2% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=5.07 ppm (s, 1H, α-CH); 6.33 ppm (s, 2H,2×aryl-H); 6.38 ppm (s, 1H, aryl-H); 6.84 ppm (d, 1H, J=46 Hz, α-NH);7.18 ppm (t, 1H, J=7.6 Hz, aryl-H); 7.30 ppm (d, 1H, J=7.6 Hz, aryl-H);7.35 ppm (m, 2H, 2×aryl-H); 7.41 ppm (d, 1H, J=7.6 Hz, aryl-H); 7.58 ppm(m, 1H, aryl-H); 7.69 ppm (m, 1H, aryl-H).

ESI-MS: molar mass (calculated for C₂₀H₁₂Cl₂NNaO₂S₂): 479.33 g/mol

Measured (negative mode): 433.9 (M-H—Na); 388.4 (M-Na—CO₂).

Example 12

(3,5-Dichlorophenylamino)-(2-methylsulfanylphenyl)acetic acid, sodiumsalt

Yield: 3.56 g (97.9% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=2.55 ppm (s, 3H, SCH₃); 4.95 ppm (m, 1H,α-CH); 6.41 ppm (s, 1H, aryl-H); 6.47 ppm (s, 2H, 2×aryl-H); 6.77 ppm(d, 1H, J=5.3 Hz, α-NH); 7.07 ppm (t, 1H, J=7.5 Hz, aryl-H); 7.15 ppm(t, 1H, J=6.8 Hz, aryl-H); 7.28 ppm (d, 1H, J=7.6 Hz, aryl-H); 7.36 ppm(d, 1H, J=7.5 Hz, aryl-H).

Example 13

(3,5-Dichlorophenylamino)-(4-methylsulfanylphenyl)acetic acid, sodiumsalt

Yield: 3.47 g (95.4% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=2.43 ppm (s, 3H, SCH₃); 4.44 ppm (d, 1H,J=4.59 Hz, α-CH); 6.46 ppm (m, 3H, 3×aryl-H); 6.64 ppm (d, 1H, J=5.3 Hz,α-NH); 7.14 ppm (d, 2H, J=8.3 Hz, aryl-H); 7.34 ppm (d, 2H, J=8.4 Hz,aryl-H).

Example 14

(3,5-Bis(trifluoromethyl)phenylamino)-(dibenzothiophen-4-yl)acetic acid,sodium salt

Yield: 4.91 g (100% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=4.74 ppm (s, 1H, α-CH); 6.88 ppm (s, 1H,aryl-H); 7.07 ppm (s (wide), 2H, 2×aryl-H); 7.25 ppm (d, 1H, J=3.7 Hz,α-NH); 7.45 ppm (m, 3H, 3×aryl-H); 7.57 ppm (d, 1H, J=7.6 Hz, aryl-H);7.97 ppm (d, 1H, J=6.8 Hz, aryl-H); 8.16 ppm (d, 1H, J=7.5 Hz, aryl-H);8.28 ppm (s, 1H, aryl-H).

ESI-MS: molar mass (calculated for C₂₂H₁₂F₆NNaO₂S): 491.39 g/mol

Measured (negative mode): 467.9 (M-H—Na); 424.3 (M-Na—CO₂).

General Synthesis Method for the Production of the CorrespondingHydrochloride Salts of the Compounds of the General Formula I:

10 mmol of the particular substituted 2-arylaminoacetic acid compound orof the particular substituted 2-heteroarylaminoacetic acid compound ofthe general formula I were dissolved in 20 ml of butanone, cooled in anice bath under a protective gas atmosphere, for example nitrogen, and 10mmol of trimethylsilyl chloride and, in a single portion, 10 mmol ofwater were added. After stirring overnight, the precipitated solid wasfiltered out, washed with a little butanone and then with diethyl ether.The hydrochloride salts were obtained as colourless solids.

Example 15

(Dibenzofuran-4-yl)-(3,5-dichlorophenylamino)acetic acid, hydrochloride

Yield: 0.93 g (2.2% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=5.85 ppm (d, 1H, J=4.5 Hz, α-CH); 6.64 ppm(s, 1H, aryl-H); 6.76 ppm (s, 2H, 2×aryl-H); 7.17 ppm (d, 1H, J=8.4 Hz,α-NH); 7.43 ppm (t, 2H, J=7.6 Hz, 2×aryl-H); 7.55 ppm (m, 2H, 2×aryl-H);7.76 ppm (d, 1H, J=8.3 Hz, aryl-H); 8.13 ppm (d, 1H, J=7.5 Hz, aryl-H);8.16 ppm (d, 1H, J=7.5 Hz, aryl-H).

ESI-MS: molar mass (calculated for C₂₀H₁₄Cl₃NO₃): 422.70 g/mol

Measured (negative mode): 385.9 (M-HCl—H); 340.3 (M-CO₂).

Example 16

(Dibenzothiophen-4-yl)-(3,5-dichlorophenylamino)acetic acid,hydrochloride

Yield: 4.35 g (99.1% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=5.47 ppm (d, 1H, J=4.9 Hz, α-CH); 6.63 ppm(s, 1H, aryl-H); 6.72 ppm (s, 2H, 2×aryl-H); 7.15 ppm (d, 1H, J=5.6 Hz,α-NH); 7.48-7.58 ppm (m, 3H, 3×aryl-H); 7.68 ppm (d, 1H, J=6.8 Hz,aryl-H); 8.04 ppm (m, 1H, aryl-H); 8.36 ppm (m, 2H, 2×aryl-H); 13.41 ppm(s (wide), 1H, CO₂H).

Example 17

(Dichlorophenylamino)-(2-methylsulfanylphenyl)acetic acid, hydrochloride

Yield: 2.82 g (74.5% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=2.54 ppm (s, 3H, SCH₃); 5.54 ppm (d, 1H,J=3.7 Hz, α-CH); 6.62 ppm (m, 2H, 2×aryl-H); 6.65 ppm (m, 1H, aryl);7.13 ppm (d, 1H, J=7.5 Hz, α-NH); 7.22 ppm (t, 1H, J=Hz, 6.7 Hz,aryl-H); 7.34 ppm (m, 1H, aryl-H); 7.46 ppm (d, 1H, J=6.7 Hz, aryl-H).

Example 18

(3,5-Dichlorophenylamino)-(4-methylsulfanylphenyl)acetic acid,hydrochloride

Yield: 2.89 g (76.4% of theoretical)

¹H-NMR (d₆-DMSO_(ext.)): δ=2.46 ppm (s, 3H, SCH₃); 5.18 ppm (d, 1H,J=5.6 Hz, α-CH); 6.62 ppm (t, 1H, J=1.9 Hz, aryl-H); 6.68 ppm (s, 2H,2×aryl-H); 6.93 ppm (d, 1H, J=7.2 Hz, α-NH); 7.26 ppm (d, 2H, J=8.3 Hz,aryl-H); 7.42 ppm (d, 2H, J=8.2 Hz, aryl-H).

Pharmacological Data

(a) Receptor Binding Study (GlycineB Binding Site of the NMDA ReceptorChannel)

The affinity of the compounds of the general formula I used according tothe invention for the glycine binding site of the NMDA receptor channelwas determined as described above and stated in Table 2 below as thepercentage fraction of the bound radioactive ligand which is displacedfrom its specific binding at a concentration of 10 μM of the compound ofthe general formula I to be tested.

The investigated compounds of the general formula I exhibited excellentaffinity for the glycine-binding site of the NMDA receptor channel. Thevalues for some selected compounds are shown in Table 2 below.

TABLE 2 Compound according to Example Inhibition %  2 33  5 26  6 87  829 10 38 11 25 12 39 13 83(b) Formaldehyde Test (Mouse)

The analgesic action of the compounds of the general formula I usedaccording to the invention was determined as described above. Thecompounds investigated in each case exhibited moderate to stronginhibition of the formaldehyde-induced nociception.

The values for some selected compounds are stated in the Table 3 below:

TABLE 3 Compound according to Example Inhibition (at dose)  6 31% (at46.4 mg/kg) 12 66% (at 31.6 mg/kg)

The forgoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations fallingwithin the scope of the appended claims and equivalents thereof.

1. A pharmaceutical formulation comprising at least one substituted2-arylaminoacetic acid compound corresponding to formula I,

wherein R¹ denotes a phenyl residue which is identically substituted inthe 3,5-position, wherein the substituents are selected from the groupconsisting of F, Cl, Br, I, OH, SH, unsubstituted C₁₋₆ alkyl,unsubstituted C₁₋₆ alkoxy, C₁₋₆ perfluoroalkyl, C₁₋₆ perfluoroalkoxy,unsubstituted C₁₋₆ alkylsulfanyl, C₁₋₆ perfluoroalkylsulfanyl,unsubstituted phenylsulfanyl, unsubstituted cyclopentyl andunsubstituted cyclohexyl, R² denotes a residue which is selected fromthe group consisting of dibenzofuran-4-yl, dibenzothiophen-4-yl,phenoxathiin-4-yl, thianthren-1-yl, 2-methylsulfanylphenyl,3-methylsulfanylphenyl and 4-methylsulfanylphenyl, or an acid, base or asalt thereof, and a pharmaceutically acceptable adjuvant.
 2. Thepharmaceutical formulation of claim 1, wherein said compound is presentin the form of an acid.
 3. The pharmaceutical formulation of claim 1,wherein said compound is present in the form of a base.
 4. Thepharmaceutical formulation of claim 1, wherein said compound is presentin the form of a sodium salt or a hydrochloride salt.
 5. Thepharmaceutical formulation of claim 1, wherein said compound is presentin the form of a pure enantiomer or pure diastereoisomer.
 6. Thepharmaceutical formulation of claim 1, wherein said compound is presentin the form of a mixture of stereoisomers.
 7. The pharmaceuticalformulation of claim 1, wherein said compound is present in the form ofa racemic mixture.
 8. The pharmaceutical formulation of claim 1, whereinR² is selected from the group consisting of dibenzofuran-4-yl,dibenzothiophen-4-yl, phenoxathiin-4-yl and thianthren-1-yl.
 9. Thepharmaceutical formulation of claim 1, wherein the compoundcorresponding to formula I is selected from the group consisting of:(dibenzofuran-4-yl)-(3,5-dichlorophenylamino)acetic acid,(dibenzothiophen-4-yl)-(3,5-dichlorophenylamino)acetic acid,(3,5-dichlorophenylamino)-(phenoxathiin-4-yl)acetic acid,(3,5-dichlorophenylamino)-(thianthren-1-yl)acetic acid,(3,5-dichlorophenylamino)-(2-methylsulfanylphenyl)acetic acid,(3,5-dichlorophenylamino)-(4-methylsulfanylphenyl)acetic acid and(3,5-bis(trifluoromethyl)phenylamino)-(dibenzothiophen-4-yl)acetic acid.10. The pharmaceutical formulation of claim 1, wherein said compound ispresent in an amount pharmaceutically effective for treating pain. 11.The pharmaceutical formulation of claim 1, wherein said compound ispresent in an amount pharmaceutically effective for treating chronicpain.
 12. The pharmaceutical formulation of claim 1, wherein saidcompound is present in an amount pharmaceutically effective for treatingneuropathic pain.